Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors

A. S. Muerhoff, D. E. Williams, N. O. Reich, C. A. CaJacob, P. R. Ortiz de Montellano, B. S S Masters

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Terminal acetylenic fatty acid mechanism-based inhibitors (Ortiz de Montellano, P.R., and Reich, N.O. (1984) J. Biol. Chem. 259, 4136-4141) were used as probes in determining the substrate specificity of rabbit lung cytochrome P-450 isozymes of pregnant animals in both microsomes and reconstituted systems. Lung microsomal and reconstituted P-450 form 5-catalyzed lauric acid ω- and (ω-1)-hydroxylase activities were inhibited by a 12-carbon terminal acetylenic fatty acid, 11-dodecynoic acid (11-DDYA), and an 18-carbon terminal acetylenic fatty acid, 17-octadecynoic acid (17-ODYA). Rabbit lung microsomal lauric acid ω-hydroxylase activity was more sensitive to inhibition by 11-DDYA than was (ω-1)-hydroxylase activity. In reconstituted systems containing purified P-450 form 5, both ω- and (ω-1)-hydroxylation of lauric acid were inhibited in parallel when either 11-DDYA or 17-ODYA was used. These data suggest the presence of at least two P-450 isozymes in rabbit lung microsomes capable of lauric acid ω-hydroxylation. This is the first report indicating the multiplicity of lauric acid hydroxylase in lung microsomes. Lung microsomal prostaglandin ω-hydroxylation, mediated by the pregnancy-inducible P-450(PG-ω) (Williams, D.E., Hale, S.E., Okita, R.T., and Masters, B.S.S. (1984) J. Biol. Chem. 259, 14600-14608) was subject to inhibition by 17-ODYA only, whereas 11-DDYA acid was not an effective inhibitor of this hydroxylase. We have recently developed a new terminal acetylenic fatty acid, 12-hydroxy-16-heptadecynoic acid (12-HHDYA), that contains a hydroxyl group at the ω-6 position. We show that 12-HHDYA possesses a high degree of selectivity for the inactivation of rabbit lung microsomal prostaglandin ω-hydroxylase activity which cannot be obtained with the long chain acetylenic inhibitor, 17-ODYA. In addition, 12-HHDYA has no effect on lauric acid ω- or ω-1-hydroxylation or on benzphetamine N-demethylation. The development of this new terminal acetylenic fatty acid inhibitor provides us with a useful tool with which to study the physiological role of prostaglandin ω-hydroxylation in the rabbit lung during pregnancy.

Original languageEnglish (US)
Pages (from-to)749-756
Number of pages8
JournalJournal of Biological Chemistry
Volume264
Issue number2
StatePublished - 1989
Externally publishedYes

Fingerprint

lauric acid
Hydroxylation
Prostaglandins
Mixed Function Oxygenases
Fatty Acids
Rabbits
Oxidation
Lung
Cytochrome P-450 CYP4A
Microsomes
Isoenzymes
Carbon
Benzphetamine
Hydroxyl Radical
Cytochrome P-450 Enzyme System
Animals
Pregnancy
2-hexadecynoic acid
Substrate Specificity
Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Muerhoff, A. S., Williams, D. E., Reich, N. O., CaJacob, C. A., Ortiz de Montellano, P. R., & Masters, B. S. S. (1989). Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors. Journal of Biological Chemistry, 264(2), 749-756.

Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors. / Muerhoff, A. S.; Williams, D. E.; Reich, N. O.; CaJacob, C. A.; Ortiz de Montellano, P. R.; Masters, B. S S.

In: Journal of Biological Chemistry, Vol. 264, No. 2, 1989, p. 749-756.

Research output: Contribution to journalArticle

Muerhoff, AS, Williams, DE, Reich, NO, CaJacob, CA, Ortiz de Montellano, PR & Masters, BSS 1989, 'Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors', Journal of Biological Chemistry, vol. 264, no. 2, pp. 749-756.
Muerhoff, A. S. ; Williams, D. E. ; Reich, N. O. ; CaJacob, C. A. ; Ortiz de Montellano, P. R. ; Masters, B. S S. / Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors. In: Journal of Biological Chemistry. 1989 ; Vol. 264, No. 2. pp. 749-756.
@article{97942d9fcfe04736bf25b4e7ea468758,
title = "Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors",
abstract = "Terminal acetylenic fatty acid mechanism-based inhibitors (Ortiz de Montellano, P.R., and Reich, N.O. (1984) J. Biol. Chem. 259, 4136-4141) were used as probes in determining the substrate specificity of rabbit lung cytochrome P-450 isozymes of pregnant animals in both microsomes and reconstituted systems. Lung microsomal and reconstituted P-450 form 5-catalyzed lauric acid ω- and (ω-1)-hydroxylase activities were inhibited by a 12-carbon terminal acetylenic fatty acid, 11-dodecynoic acid (11-DDYA), and an 18-carbon terminal acetylenic fatty acid, 17-octadecynoic acid (17-ODYA). Rabbit lung microsomal lauric acid ω-hydroxylase activity was more sensitive to inhibition by 11-DDYA than was (ω-1)-hydroxylase activity. In reconstituted systems containing purified P-450 form 5, both ω- and (ω-1)-hydroxylation of lauric acid were inhibited in parallel when either 11-DDYA or 17-ODYA was used. These data suggest the presence of at least two P-450 isozymes in rabbit lung microsomes capable of lauric acid ω-hydroxylation. This is the first report indicating the multiplicity of lauric acid hydroxylase in lung microsomes. Lung microsomal prostaglandin ω-hydroxylation, mediated by the pregnancy-inducible P-450(PG-ω) (Williams, D.E., Hale, S.E., Okita, R.T., and Masters, B.S.S. (1984) J. Biol. Chem. 259, 14600-14608) was subject to inhibition by 17-ODYA only, whereas 11-DDYA acid was not an effective inhibitor of this hydroxylase. We have recently developed a new terminal acetylenic fatty acid, 12-hydroxy-16-heptadecynoic acid (12-HHDYA), that contains a hydroxyl group at the ω-6 position. We show that 12-HHDYA possesses a high degree of selectivity for the inactivation of rabbit lung microsomal prostaglandin ω-hydroxylase activity which cannot be obtained with the long chain acetylenic inhibitor, 17-ODYA. In addition, 12-HHDYA has no effect on lauric acid ω- or ω-1-hydroxylation or on benzphetamine N-demethylation. The development of this new terminal acetylenic fatty acid inhibitor provides us with a useful tool with which to study the physiological role of prostaglandin ω-hydroxylation in the rabbit lung during pregnancy.",
author = "Muerhoff, {A. S.} and Williams, {D. E.} and Reich, {N. O.} and CaJacob, {C. A.} and {Ortiz de Montellano}, {P. R.} and Masters, {B. S S}",
year = "1989",
language = "English (US)",
volume = "264",
pages = "749--756",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "2",

}

TY - JOUR

T1 - Prostaglandin and fatty acid ω- and (ω-1)-oxidation in rabbit lung. Acetylenic fatty acid mechanism-based inactivators as specific inhibitors

AU - Muerhoff, A. S.

AU - Williams, D. E.

AU - Reich, N. O.

AU - CaJacob, C. A.

AU - Ortiz de Montellano, P. R.

AU - Masters, B. S S

PY - 1989

Y1 - 1989

N2 - Terminal acetylenic fatty acid mechanism-based inhibitors (Ortiz de Montellano, P.R., and Reich, N.O. (1984) J. Biol. Chem. 259, 4136-4141) were used as probes in determining the substrate specificity of rabbit lung cytochrome P-450 isozymes of pregnant animals in both microsomes and reconstituted systems. Lung microsomal and reconstituted P-450 form 5-catalyzed lauric acid ω- and (ω-1)-hydroxylase activities were inhibited by a 12-carbon terminal acetylenic fatty acid, 11-dodecynoic acid (11-DDYA), and an 18-carbon terminal acetylenic fatty acid, 17-octadecynoic acid (17-ODYA). Rabbit lung microsomal lauric acid ω-hydroxylase activity was more sensitive to inhibition by 11-DDYA than was (ω-1)-hydroxylase activity. In reconstituted systems containing purified P-450 form 5, both ω- and (ω-1)-hydroxylation of lauric acid were inhibited in parallel when either 11-DDYA or 17-ODYA was used. These data suggest the presence of at least two P-450 isozymes in rabbit lung microsomes capable of lauric acid ω-hydroxylation. This is the first report indicating the multiplicity of lauric acid hydroxylase in lung microsomes. Lung microsomal prostaglandin ω-hydroxylation, mediated by the pregnancy-inducible P-450(PG-ω) (Williams, D.E., Hale, S.E., Okita, R.T., and Masters, B.S.S. (1984) J. Biol. Chem. 259, 14600-14608) was subject to inhibition by 17-ODYA only, whereas 11-DDYA acid was not an effective inhibitor of this hydroxylase. We have recently developed a new terminal acetylenic fatty acid, 12-hydroxy-16-heptadecynoic acid (12-HHDYA), that contains a hydroxyl group at the ω-6 position. We show that 12-HHDYA possesses a high degree of selectivity for the inactivation of rabbit lung microsomal prostaglandin ω-hydroxylase activity which cannot be obtained with the long chain acetylenic inhibitor, 17-ODYA. In addition, 12-HHDYA has no effect on lauric acid ω- or ω-1-hydroxylation or on benzphetamine N-demethylation. The development of this new terminal acetylenic fatty acid inhibitor provides us with a useful tool with which to study the physiological role of prostaglandin ω-hydroxylation in the rabbit lung during pregnancy.

AB - Terminal acetylenic fatty acid mechanism-based inhibitors (Ortiz de Montellano, P.R., and Reich, N.O. (1984) J. Biol. Chem. 259, 4136-4141) were used as probes in determining the substrate specificity of rabbit lung cytochrome P-450 isozymes of pregnant animals in both microsomes and reconstituted systems. Lung microsomal and reconstituted P-450 form 5-catalyzed lauric acid ω- and (ω-1)-hydroxylase activities were inhibited by a 12-carbon terminal acetylenic fatty acid, 11-dodecynoic acid (11-DDYA), and an 18-carbon terminal acetylenic fatty acid, 17-octadecynoic acid (17-ODYA). Rabbit lung microsomal lauric acid ω-hydroxylase activity was more sensitive to inhibition by 11-DDYA than was (ω-1)-hydroxylase activity. In reconstituted systems containing purified P-450 form 5, both ω- and (ω-1)-hydroxylation of lauric acid were inhibited in parallel when either 11-DDYA or 17-ODYA was used. These data suggest the presence of at least two P-450 isozymes in rabbit lung microsomes capable of lauric acid ω-hydroxylation. This is the first report indicating the multiplicity of lauric acid hydroxylase in lung microsomes. Lung microsomal prostaglandin ω-hydroxylation, mediated by the pregnancy-inducible P-450(PG-ω) (Williams, D.E., Hale, S.E., Okita, R.T., and Masters, B.S.S. (1984) J. Biol. Chem. 259, 14600-14608) was subject to inhibition by 17-ODYA only, whereas 11-DDYA acid was not an effective inhibitor of this hydroxylase. We have recently developed a new terminal acetylenic fatty acid, 12-hydroxy-16-heptadecynoic acid (12-HHDYA), that contains a hydroxyl group at the ω-6 position. We show that 12-HHDYA possesses a high degree of selectivity for the inactivation of rabbit lung microsomal prostaglandin ω-hydroxylase activity which cannot be obtained with the long chain acetylenic inhibitor, 17-ODYA. In addition, 12-HHDYA has no effect on lauric acid ω- or ω-1-hydroxylation or on benzphetamine N-demethylation. The development of this new terminal acetylenic fatty acid inhibitor provides us with a useful tool with which to study the physiological role of prostaglandin ω-hydroxylation in the rabbit lung during pregnancy.

UR - http://www.scopus.com/inward/record.url?scp=0024501044&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024501044&partnerID=8YFLogxK

M3 - Article

C2 - 2910864

AN - SCOPUS:0024501044

VL - 264

SP - 749

EP - 756

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -